The Correlation between the Level of Doxorubicin-Induced Cardiac Damage and Serum Soluble Fas in an Experimental Rat Model

Abstract

Aim: This study was planned to research the relationship between doxorubicin cardiomyopathy and the soluble Fas (sFas) level. Materials and Methods: Two groups of rats were included in the study. The control group was given physiological saline, while the study group was given doxorubicin. The rats, whose blood samples were taken weekly, were sacrificed and their myocardial tissues were removed. The tissues were examined in terms of morphological changes and surface Fas expression, while the blood samples were examined in terms of sFas level. Results: In the study group, the sFas levels at 2^nd–9^th weeks were higher than those found at 1^st week before administrating the drug, and the increase at 2^nd–7^th weeks was meaningful. In addition, sFas levels were gradually increased each week during 1^st–5^th weeks when compared to the values of a previous week, and the increase during the first 4 weeks was meaningful. After the 5^th week, the values gradually decreased each week. The mean values of the study group at 1^st–8^th weeks were higher than those of the control group, and the increases at 2^nd–8^th weeks were meaningful. The severe forms of interfibrillar hemorrhage, vascular dilatation, myocardial necrosis, inflammatory infiltration, and splitting of muscle fibers occurred with 15, 15, 17.5, 20, and 22.5 mg/kg dose of medicine, respectively. Conclusions: As the tissue injury increased, the increasing cell-surface Fas expression and sFas plasma level at the acute phase of doxorubicin-related cardiotoxicity decreased. The sFas level determined at acute phase may be helpful in predicting the existing injuries and possible late-term problems.

Keywords

Cardiac - doxorubicin - fas - rat

Publikationsverlauf

Artikel online veröffentlicht:
17. Juni 2021

• References

• 1 Von Hoff DD, Layard MW, Basa P, Davis Jr HL, Von Hoff AL, Rozencweig M. et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 1979; 91: 710-7
• 2 Nousiainen T, Vanninen E, Jantunen E, Puustinen J, Remes J, Rantala A. et al. Natriuretic peptides during the development of doxorubicin-induced left ventricular diastolic dysfunction. J Intern Med 2002; 251: 228-34
• 3 Weesner KM, Bledsoe M, Chauvenet A, Wofford M. Exercise echocardiography in the detection of anthracycline cardiotoxicity. Cancer 1991; 68: 435-8
• 4 Solcia E, Ballerini L, Bellini O, Magrini U, Bertazzoli C, Tosana G. et al. Cardiomyopathy of doxorubicin in experimental animals, Factors affecting the severity, distribution and evolution of myocardial lesions. Tumori 1981; 67: 461-72
• 5 Iatropoulos MJ. Anthracycline cardiomyopathy: Predictive value of animal models. Cancer Treat Symp 1984; 3: 3-17
• 6 Podestà A, Della Torre P, Pinciroli G, Iatropoulos MJ, Brughera M, Mazué G. Evaluation of 4’-iodo-4’-deoxydoxorubicin-induced cardiotoxicity in two experimental rat models. Toxicol Pathol 1994; 22: 68-71
• 7 Allen A. The cardiotoxicity of chemotherapeutic drugs. Semin Oncol 1992; 19: 529-42
• 8 Nakamura T, Ueda Y, Juan Y, Katsuda S, Takahashi H, Koh E. Fas-mediated apoptosis in adriamycin-induced cardiomyopathy in rats:In vivo study. Circulation 2000; 102: 572-8
• 9 Ashkenazi A, Dixit VM. Death receptors: Signaling and modulation. Science 1998; 281: 1305-8
• 10 Kerr JF, Winterford CM, Harmon BV. Apoptosis. Its significance in cancer and cancer therapy. Cancer 1994; 73: 2013-26
• 11 Jäckel MC, Sellmann L, Dorudian MA, Youssef S, Füzesi L. Prognostic significance of p53/bcl-2 co-expression in patients with laryngeal squamous cell carcinoma. Laryngoscope 2000; 110: 1339-45
• 12 Cheng J, Zhou T, Liu C, Shapiro JP, Brauer MJ, Kiefer MC. et al. Protection from Fas-mediated apoptosis by a soluble form of the Fas molecule. Science 1994; 263: 1759-62
• 13 Yang X, Khosravi-Far R, Chang HY, Baltimore D. Daxx, a novel Fas-binding protein that activates JNK and apoptosis. Cell 1997; 89: 1067-76
• 14 Miyata S, Takemura G, Kosai K, Takahashi T, Esaki M, Li L. et al. Anti-Fas gene therapy prevents doxorubicin-induced acute cardiotoxicity through mechanisms independent of apoptosis. Am J Pathol 2010; 176: 687-98
• 15 Lien YC, Daosukho C, St Clair DK. TNF receptor deficiency reveals a translational control mechanism for adriamycin-induced Fas expression in cardiac tissues. Cytokine 2006; 33: 226-30
• 16 Perik PJ, De Vries EG, Boomsma F, Messerschmidt J, Van Veldhuisen DJ, Sleijfer DT. et al. The relation between soluble apoptotic proteins and subclinical cardiotoxicity in adjuvant-treated breast cancer patients. Anticancer Res 2006; 26: 3803-11
• 17 Yamaoka M, Yamaguchi S, Suzuki T, Okuyama M, Nitobe J, Nakamura N. et al. Apoptosis in rat cardiac myocytes induced by Fas ligand: Priming for Fas-mediated apoptosis with doxorubicin. J Mol Cell Cardiol 2000; 32: 881-9
• 18 Niu J, Azfer A, Deucher MF, Goldschmidt-Clermont PJ, Kolattukudy PE. Targeted cardiac expression of soluble Fas prevents the development of heart failure in mice with cardiac-specific expression of MCP-1. J Mol Cell Cardiol 2006; 40: 810-20
• 19 Pichon MF, Labroquère M, Rezaï K, Lokiec F. Variations of soluble fas and cytokeratin 18-Asp 396 neo-epitope in different cancers during chemotherapy. Anticancer Res 2006; 26: 2387-92